Discovery of thienopyrimidine-based FLT3 inhibitors from the structural modification of known IKKβ inhibitors

Bioorg Med Chem Lett. 2014 Jun 15;24(12):2655-60. doi: 10.1016/j.bmcl.2014.04.058. Epub 2014 Apr 24.

Abstract

Inactivation of the NF-κB signaling pathway by inhibition of IKKβ is a well-known approach to treat inflammatory diseases such as rheumatoid arthritis and cancer. Thienopyrimidine-based analogues were designed through modification of the known IKKβ inhibitor, SPC-839, and then biologically evaluated. The resulting analogues had good inhibitory activity against both nitric oxide and TNF-α, which are well-known inflammatory responses generated by activated NF-κB. However, no inhibitory activity against IKKβ was observed with these compounds. The thienopyrimidine-based analogues were subsequently screened for a target kinase, and FLT3, which is a potential target for acute myeloid leukemia (AML), was identified. Thienopyrimidine-based FLT3 inhibitors showed good inhibition profiles against FLT3 under 1μM. Overall, these compounds represent a promising family of inhibitors for future development of a treatment for AML.

Keywords: Acute myeloid leukemia (AML); Anti-inflammation; FLT3; IKKβ; Thienopyrimidine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Enzyme Activation / drug effects
  • Humans
  • I-kappa B Kinase / antagonists & inhibitors*
  • I-kappa B Kinase / chemistry
  • Maleimides / chemistry
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Quinazolines / chemistry
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology
  • fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*

Substances

  • Maleimides
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Quinazolines
  • SPC-839
  • Small Molecule Libraries
  • thienopyrimidine
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3
  • I-kappa B Kinase